Cyclooxygenase-1 as an anti-stroke target: potential inhibitor identification and non-synonymous single nucleotide polymorphism analysis
- Authors: Muronzi, Tendai
- Date: 2020
- Subjects: Cerebrovascular disease , Cerebrovascular disease -- Treatment , Cerebrovascular disease -- Chemotherapy , Cyclooxygenases , High throughput screening (Drug development) , Drug development , Molecular dynamics , South African Natural Compounds Database , ZINC database
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/143404 , vital:38243
- Description: Stroke is the third leading cause of death worldwide, with 87% of cases being ischemic stroke. The two primary therapeutic strategies to reduce post-ischemic brain damage are cellular and vascular approaches. The vascular strategy aims to rapidly re-open obstructed blood vessels, while the cellular approach aims to interfere with the signalling pathways that facilitate neuron damage and death. Unfortunately, popular vascular treatments have adverse side effects, necessitating the need for alternative chemotherapeutics. In this study, cyclooxygenase-1 (COX-1), which plays a significant role in the post- ischemic neuroinflammation and neuronal death, was targeted for identification of novel drug compounds and to assess the effect of nsSNPs on its structure and function. In a drug discovery part, ligands from the South African Natural Compounds Database (SANCDB-https://sancdb.rubi.ru.ac.za/) and ZINC database (http://zinc15.docking.org/) were used for high-throughput virtual screening (HVTS) against COX-1. Additionally, five nsSNPs were being investigated to assess their impact on protein structure and function. Three of these SNPs were in the COX-1 dimer interface. Molecular docking and molecular dynamics simulations revealed asymmetric nature of the protein. Several ligands, peculiar to each monomer, exhibited favourable binding energies in the respective active sites. SNP analysis indicated effects on inter-monomer interactions and protein stability.
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- Date Issued: 2020
In silico study of Plasmodium 1-deoxy-dxylulose 5-phosphate reductoisomerase (DXR) for identification of novel inhibitors from SANCDB
- Authors: Diallo, Bakary N'tji
- Date: 2018
- Subjects: Plasmodium 1-deoxy-dxylulose 5-phosphate reductoisomerase , Isoprenoids , Plasmodium , Antimalarials , Malaria -- Chemotherapy , Molecules -- Models , Molecular dynamics , South African Natural Compounds Database
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/64012 , vital:28523
- Description: Malaria remains a major health concern with a complex parasite constantly developing resistance to the different drugs introduced to treat it, threatening the efficacy of the current ACT treatment recommended by WHO (World Health Organization). Different antimalarial compounds with different mechanisms of action are ideal as this decreases chances of resistance occurring. Inhibiting DXR and consequently the MEP pathway is a good strategy to find a new antimalarial with a novel mode of action. From literature, all the enzymes of the MEP pathway have also been shown to be indispensable for the synthesis of isoprenoids. They have been validated as drug targets and the X-ray structure of each of the enzymes has been solved. DXR is a protein which catalyses the second step of the MEP pathway. There are currently 255 DXR inhibitors in the Binding Database (accessed November 2017) generally based on the fosmidomycin structural scaffold and thus often showing poor drug likeness properties. This study aims to research new DXR inhibitors using in silico techniques. We analysed the protein sequence and built 3D models in close and open conformations for the different Plasmodium sequences. Then SANCDB compounds were screened to identify new potential DXR inhibitors with new chemical scaffolds. Finally, the identified hits were submitted to molecular dynamics studies, preceded by a parameterization of the manganese atom in the protein active site.
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- Date Issued: 2018
Structure and interaction studies of beta-amyloid in the search for new lead compounds for the treatment of Alzheimer’s disease
- Authors: Mtini, Onke
- Date: 2020
- Subjects: Alzheimer's disease -- Chemotherapy , Alzheimer's disease -- Treatment , Amyloid beta-protein , Oxidative stress , Protein binding , South African Natural Compounds Database
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/167574 , vital:41493
- Description: Alzheimer’s disease (AD) is the most devastating neurodegenerative disorder that effects the aging population worldwide. In this study three hypotheses of AD are explored, the β-amyloid cascade hypothesis, the β-amyloid metal binding hypothesis and the oxidative stress hypothesis are explored. In the first case compounds from the South African Natural Compounds Database (SANCDB) are docked to models of β-amyloid fibrils and the properties of these fibrils under pulling simulations are compared to a known small molecule disruptor of β-amyloid, wgx-50. In these simulations SANCDB compounds are identified that disrupt β-amyloid in a similar manner to wgx-50. In these simulations the disruption to the free energy of binding of chains to the fibrils is quantified. For metal binding and oxidative stress hypotheses, problems in simulation arise due to only fragments of β-amyloid being present in the Research Collaboratory for Structural Bioinformatics protein data bank (RCSB PDB), as determined from NMR experiments. In this work, β-amyloid is set up under periodic boundary conditions to simulate a fibril under reasonable computational time. Within these periodic boundary conditions, β-amyloid has been solvated in copper and zinc rich environments and diffusion of these metals around the fibrils has been explored. The localization of these metals (in simulation only using van der Waal’s and electrostatic terms) around the fibril has led us to explore other possible metal binding sites. Metal bound to the infinite fibril has been optimized at the QM/MM level and some of the reactive oxygen species in the presence of the fibril are quantified.
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- Date Issued: 2020
Targeting allosteric sites of Escherichia coli heat shock protein 70 for antibiotic development
- Authors: Okeke, Chiamaka Jessica
- Date: 2019
- Subjects: Heat shock proteins , Escherichia coli , Allosteric proteins , Antibiotics , Molecular chaperones , Ligands (Biochemistry) , Molecular dynamics , Principal components analysis , South African Natural Compounds Database
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/115998 , vital:34287
- Description: Hsp70s are members of the heat shock proteins family with a molecular weight of 70-kDa and are the most abundant group in bacterial and eukaryotic systems, hence the most extensively studied ones. These proteins are molecular chaperones that play a significant role in protein homeostasis by facilitating appropriate folding of proteins, preventing proteins from aggregating and misfolding. They are also involved in translocation of proteins into subcellular compartments and protection of cells against stress. Stress caused by environmental or biological factors affects the functionality of the cell. In response to these stressful conditions, up-regulation of Hsp70s ensures that the cells are protected by balancing out unfolded proteins giving them ample time to repair denatured proteins. Hsp70s is connected to numerous illnesses such as autoimmune and neurodegenerative diseases, bacterial infection, cancer, malaria, and obesity. The multi-functional nature of Hsp70s predisposes them as promising therapeutic targets. Hsp70s play vital roles in various cell developments, and survival pathways, therefore targeting this protein will provide a new avenue towards the discovery of active therapeutic agents for the treatment of a wide range of diseases. Allosteric sites of these proteins in its multi-conformational states have not been explored for inhibitory properties hence the aim of this study. This study aims at identifying allosteric sites that inhibit the ATPase and substrate binding activities using computational approaches. Using E. coli as a model organism, molecular docking for high throughput virtual screening was carried out using 623 compounds from the South African Natural Compounds Database (SANCDB; https://sancdb.rubi.ru.ac.za/) against identified allosteric sites. Ligands with the highest binding affinity (good binders) interacting with critical allosteric residues that are druggable were identified. Molecular dynamics (MD) simulation was also performed on the identified hits to assess for protein-inhibitor complex stability. Finally, principal component analysis (PCA) was performed to understand the structural dynamics of the ligand-free and ligand-bound structures during MD simulation.
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- Date Issued: 2019